Multiple sclerosis (MS) is the most common neurological disease of young adults in the United States, with a prevalence estimated to be 400,000 and with annual medical expenses and lost productivity costs of approximately $9.5 billion. We hypothesize (Central Hypothesis) that microvascular abnormalities (a consequence of the perivenous inflammation known to occur in MS) are a final common pathway leading to injury of the central nervous system. This hypothesis is based upon preliminary data we have gathered and is supported by pathological evidence of such injury. Ensuing microvascular ischemic damage to axons/neurons interferes with normal iron homeostasis, resulting in accumulation of excess iron in the deep gray matter. Neurocognitive deficits and fatigue experienced by MS patients are consequences of oxidative injury by iron accretion in the basal ganglia and thalamus. To test this hypothesis, we propose four Specific Aims: Specific Aim 1 defines baseline perfusion (cerebral blood flow; cerebral blood volume; mean transit time), magnetic resonance (MR) spectroscopy (N-acetyl aspartate), and quantitative MR metrics (diffusion tensor; diffusion kurtosis; magnetic field correlation; structural volume) at high-field (3 Tesla) in 30 early relapsing remitting MS patients and age/sex matched controls. Specific Aim 2 measures baseline cognitive impairment and fatigue and associates these results with quantitative MR metrics of the deep gray matter. Specific Aim 3 associates, over a 4 year duration, deep gray matter iron accumulation with both damage to these structures and progressive brain parenchymal loss. Specific Aim 4 associates, over a 4 year duration, the decline in neurocognitive function and fatigue with deep gray matter injury. This research will provide new insights into the pathophysiology of Multiple Sclerosis and common morbidities (cognitive decline and fatigue) experienced by MS patients. It will result in more appropriate measures to detect and quantitate the effect of the disease and will provide a rationale for innovative treatment regimes. [unreadable] [unreadable] [unreadable]